The present invention provides pharmaceutical compositions comprising a stable water-insoluble complex composed of an amorphous therapeutically active compound (e.g. a drug) dispersed in an ionic polymer. The complexes according to the present invention provide significant increases in bioavailability of poorly soluble therapeutically active compounds.
The bioavailability of a therapeutically active compound is generally affected by (i) the solubility/dissolution rate of the compound, and (ii) the partition coefficient/permeability of the compound through a subject""s gastrointestinal membrane. The major cause of poor bioavailability of a therapeutically active compound is the poor solubility/dissolution rate of said compound. Poor bioavailability is also often accompanied with undesirably high rates of patient variability and unpredictable dose/therapy effects due to erratic absorption of the therapeutically active compound (e.g. drug) by the patient.
Several techniques are used to improve the bioavailability of poorly soluble therapeutically active compounds. These techniques are summarized below.
1. Particle Size Reduction
A poorly soluble therapeutically active compound often is mechanically ground to reduce the particle size of the compound and thereby increase the surface area. See Lachman et al., The Theory and Practice of Industrial Pharmacy, Chapter 2, p. 45 (1986). Particle size reduction into micron size particles can be achieved using a jet mill. The mean particle size obtained by the jet mill is typically in the range of 1-10 xcexcm. Similarly, wet milling of a therapeutically active compound in the presence of protective colloids or polymers typically yields particle sizes of compound in the range of about 300-800 nm. According to this technique, a therapeutically active compound and a polymer are dispersed in water and ground by grinding media such as tiny beads (0.2-0.5 mm). See U.S. Pat. No. 5,494,683. Particle size reduction however, can only improve the dissolution rate of the therapeutically active compound, but not the total amount of compound in solution at equilibrium.
2. Solid Dispersion
2.1 Fusion Method
According to this technique, a therapeutically active compound is dispersed into a non-ionic polymer to form a solid dispersion. Typically, the non-ionic polymer (e.g. Pluronic(copyright) and Polyethylene Glycol) is melted to a temperature above its melting point and the therapeutically active compound is dissolved, with stirring, into the molten polymer. See U.S. Pat. No. 5,281,420. The resulting molten mass is then cooled to room temperature. As a result of this process, the therapeutically active compound is fused into the polymer and on cooling, precipitates out in amorphous form. The amorphous form of the compound generally has a faster dissolution rate then the initial crystalline form of the compound. Thus, by rendering the compound in amorphous form this process improves bioavailability. However, due to the greater aqueous solubility and low melting point of non-ionic polymers, the amorphous form of the therapeutically active compound, can not maintain its stability and eventually converts back to the crystalline form after exposure to high humidity and elevated temperatures often encountered during long term storage. See Yoshioka et al., J. Pharm. Sci. 83:1700-1705 (1994). Therefore, this technique is not suitable for most dosage forms of therapeutically active compounds, and certainly not for those therapeutically active compounds having poor solubility.
2.2 Co-precipitation
In another existing method for improving the bioavailability of a poorly soluble therapeutically active compound, the compound and a non-ionic hydrophilic polymer, such as polyvinyl pyrrolidone, are dissolved in an organic solvent. The solvent is removed by evaporation during which the therapeutically active compound precipitates into the hydrophilic polymer matrix. See, H. G. Britain, Physical Characterization of Pharmaceutical Solids, Drugs and the Pharmaceutical Sciences, Vol. 70 (Marcel Dekker, Inc., N.Y., 1995). Due to the hygroscopic nature and aqueous solubility of the polymer, this type of polymer does not protect the amorphous form of the therapeutically active compound from heat and moisture. Thus, the therapeutically active compound in the hydrophilic polymer matrix does not stay in amorphous form and eventually converts to a crystalline form during storage. Therefore, this approach also is not practical to improve the bioavailability of poorly soluble therapeutically active compounds.
3. Self-Emulsifying Drug Delivery System (SEDDS)
In this system, a therapeutically active compound is dissolved in a mixture of a suitable oil and emulsifier. The resultant lipid formulation, upon exposure to gastrointestinal fluids, forms a very fine emulsion or microemulsion. Due to high surface area of the oil globules, the bioavailability of a poorly soluble therapeutically active compound dissolved in such oil is significantly increased. See, P. P. Constantinides, Pharm. Res. 12(11): 1561-1572 (1995). The key requirement for use of this system is that the therapeutically active compound must be soluble in oil and once dissolved in oil, must remain in stable form in the solution. SEDDS is thus not a useful alternative for most therapeutically active compounds due to the limited solubility and unsatisfactory stability of these compounds in an oil-based solution.
We have surprisingly found that when a poorly soluble therapeutically active compound (typically in crystalline form) is molecularly dispersed in a water-insoluble ionic polymer having a molecular weight greater than about 80,000 D and a glass transition temperature equal to or greater than about 50xc2x0 C., the physical stability of the compound (now in amorphous form) is maintained for long periods of time even under high humidity and temperature storage conditions. Due to the high molecular weight and high glass transition temperature of the ionic polymer, as well as its relative insolubility in water, the ionic polymer immobilizes the therapeutically active compound in its amorphous form thereby providing excellent stability of compound which is superior to that afforded by currently available methods. In addition, due to the increased solubility of the compound in the compound/polymer complex, the bioavailability of the therapeutically active compound is also significantly increased. This method is therefore particularly useful for improving the bioavailability of poorly soluble therapeutically active compounds.
The present invention provides a pharmaceutical composition comprising a stable, water-insoluble complex composed of a carrier macromolecule that is a water-insoluble ionic polymer having a molecular weight greater than about 80,000 D and a glass transition temperature equal to or greater than about 50xc2x0 C., and an amorphous therapeutically active compound, wherein the therapeutically active compound is incorporated or dispersed in the ionic polymer in stable amorphous form to yield a compound/polymer complex. Another aspect of this invention is the water-insoluble compound/polymer complex. The complex of the invention is formed by the microprecipitation of the therapeutically active compound in the ionic carrier.
The compound/polymer complex of the invention may be in the form of a solid (e.g. a paste, granules, a powder) which can be filled into capsules or compressed into tablets. The powdered form of the complex may also be pulverized or micronized sufficiently to form stable liquid suspensions or semi-solid dispersions. The complex of the invention may be sterilized, such as by gamma irradiation or electron beam irradiation, prior to administration in vivo for parenteral applications.